Inflammatory interstitial nephritis, either as a primary or secondary condition, plays a central role in the development of all forms of chronic renal failure. We have been studying this problem with a murine model of immune-mediated interstitial nephritis called anti-tubular basement membrane (alpha-TBM) disease. Immune injury is produced in this model by T cells and antibodies (alpha-TBM-Ab) which are directed at the epithelial target antigen (3M-1) expressed by the tubulointerstitium. Histologic damage occurs through the formation of interstitial mononuclear cell infiltrates that subsequently induce progressive fibrogenesis. The purpose of this grant is to determine how the nephritogenic immune response recognizes 3M-1 domains and interactively changes the cell biology of 3M-1 bound by alpha3M-1-Ab. I will also analyze changes in tubular epithelial (MCT) growth, and the expression of extracellular matrix and 3M-1/MHC antigen genes induced by 3M-1 specific and non-specific immune products. The techniques of Northern hybridization, nuclear runoff transcription, in situ hybridization, solid-phase radioimmunoassay, cytofluorography, immunofluorescence microscopy, gene transfection and reporter gene expression assays will be collectively utilized to address selected issues regarding the biology of tubulointerstitial epithelial cell function, mechanisms of antigen- recognition and immune-activated renal fibrogenesis. I believe these studies, on balance will provide new and useful information that eventually can be employed in subsequent therapeutic strategies which might favorably alter the natural history of immune-mediated interstitial injury.